The present invention relates to biomaterials.
A xe2x80x9cbiomaterialxe2x80x9d is a non-living material used in a medical device which is intended to interact with biological systems. Such materials may be relatively xe2x80x9cbioinertxe2x80x9d, xe2x80x9cbiocompatiblexe2x80x9d, xe2x80x9cbioactivexe2x80x9d or xe2x80x9cresorbablexe2x80x9d, depending on their biological response in vivo.
Bioactive materials are a class of materials each of which when in vivo elicits a specific biological response that results in the formation of a bond between living tissue and that material. Bioactive materials are also referred to as surface reactive biomaterials. Biomaterials may be defined as materials suitable for implantation into a living organism. L. L. Hench has reviewed biomaterials in a scientific paper published in Science, Volume 208, May 1980, pages 826-831. Biomaterials which are relatively inert may cause interfacial problems when implanted and so considerable research activity has been directed towards developing materials which are bioactive in order to improve the biomaterial-tissue interface.
Known bioactive materials include hydroxyapatite (HA), some glasses and some glass ceramics. Both bioactive glasses and bioactve glass ceramics form a biologically active layer of hydroxycarbonateapatite (HCA) when implanted. This layer is equivalent chemically and structurally to the mineral phase in bone and is responsible for the interfacial bonding between bone and the bioactive material. The properties of these bioactive-materials are described by L. L. Hench in the Journal of the American Ceramic Society, Volume 74 Number 7, 1991, pages 1487-1510. The scientific literature on bioactive materials often uses the terms HA and HCA on an interchangeable basis. In this patent specification, the materials HA and HCA are collectively referred to as apatite.
Li et al. have reported the deposition of apatite on silica gel in the Journal of Biomedical Materials Research, Volume 28, 1994, pages 7-15. They suggest that a certain density of silanol (SiOH) groups is necessary to trigger the heterogeneous nucleation of hydroxyapatite. An apatite layer did not develop on the surface of a silica glass sample and this is attributed to the lower density of surface silanol groups compared with silica gel.
Thick films of apatite have previously been deposited on silicon single crystal wafers by placing the wafers in close proximity to a plate of apatite and wollastonite-containing glass dipped into a physiological solution at 36xc2x0 C., as described by Wang et al. in the Journal of Materials Science: Materials In Medicine, Volume 6, 1995, pages 94-104. A physiological solution, also known as a simulated body fluid (SBF), is a solution containing ion concentrations similar to those found in the human body and is widely used to mimic the behaviour of the body in in vitro tests of bioactivity. Wang et al. reported the growth of apatite on (111) Si wafers but reported that xe2x80x9chardly anyxe2x80x9d apatite could be grown on (100) Si wafers. The silicon wafer itself is not bioactive. Wang et al. state that xe2x80x9cSi does not play any special role in the growth of (the) apatite film except that Si atoms on the substrate can bond strongly with oxygen atoms in apatite nuclei to form interfaces with low energyxe2x80x9d. The presence of the apatite and wollastonite containing glass is required to induce the deposition of the apatite. Indeed, this so-called xe2x80x9cbiomimetic processxe2x80x9d whereby a bioactive material is used to treat another material has been shown to induce apatite growth on a wide variety of bioinert materials, as reported by Y. Abe et al. in the Journal of Materials Science: Materials In Medicine, Volume 1, 1990, pages 233 to 238.
There is a long felt want for the ability to use silicon based integrated circuits within the human body both for diagnostic and therapeutic purposes. Silicon has been reported to exhibit a poor biocompatibility in blood, Kanda et al. in Electronics Letters, Volume 17, Number 16, 1981, pages 558 and 559, and in order to protect integrated circuits from damage in biological environments encapsulation by a suitable material is currently required. Medical applications for silicon based sensors are described in a paper by Engels et al. in the Journal of Physics E: Sci. Instrum., Volume 16, 1983, pages 987 to 994.
The present invention provides bioactive silicon characterized in that the silicon is at least partly crystalline.
Bioactive silicon provides the advantage over other bioactive materials that it is compatible with silicon based integrated circuit technology. It has the advantage over non-bioactive silicon that it exhibits a greater degree of biocompatibility. In addition, bioactive silicon may be used for forming a bond to bone or vascular tissue of a living animal. Bioactive silicon may provide a material suitable for use as a packaging material in miniaturised packaging applications.
The bioactive nature of the silicon may be demonstrated by the immersion of the material in a simulated body fluid held at a physiological temperature, such immersion producing a mineral deposit on the bioactive silicon. The mineral deposit may be apatite. The apatite deposit may be continuous over an area greater than 100 xcexcm2. The bioactive silicon may be at least partially porous silicon. The porous silicon may have a porosity greater than 4% and less than 70%.
Bulk crystalline silicon can be rendered porous by partial electrochemical dissolution in hydrofluoric acid based solutions, as described in U.S. Pat. No. 5,348,618. This etching process generates a silicon structure that retains the crystallinity and the crystallographic orientation of the original bulk material. The porous silicon thus formed is a form of crystalline silicon. At low levels of porosity, for example less than 20%, the electronic properties of the porous silicon resemble those of bulk crystalline silicon.
Porous silicon may be subdivided according to the nature of the porosity. Microporous silicon contains pores having a diameter less than 20 xc3x85; mesoporous silicon contains pores having a diameter in the range 20 xc3x85 to 500 xc3x85; and macroporous silicon contains pores having a diameter greater than 500 xc3x85. The bioactive silicon may comprise porous silicon which is either microporous or mesoporous.
Silicon has never been judged a promising biomaterial, in contrast with numerous metals, ceramics and polymers, and has never been judged capable of exhibiting bioactive behaviour. Indeed, no semiconductors have been reported to be bioactive. Silicon is at best reported to be relatively bioinert but generally exhibits poor biocompatibility. Despite the advances made in miniaturisation of integrated circuitry, silicon VLSI technology is still under development for invasive medical and biosensing applications, as described by K. D. Wise et al. in xe2x80x9cVLSI in Medicinexe2x80x9d edited by N. G. Einspruch et at., Academic Press, New York, 1989, Chapter 10 and M. Madou et al. in Appl. Biochem. Biotechn., Volume 41, 1993, pages 109-128.
The use of silicon structures for biological applications is known. International patent application PCT/US95/02752 having an International Publication Number WO 95/24472 describes a capsule having end faces formed from a perforated amorphous silicon structure, whose pores are large enough to allow desired molecular products through but which block the passage of larger immunological molecules, to provide immunological isolation of cells contained therein. No evidence as to the biocompatibility of the silicon structure is provided, and workers skilled in the field of biocompatible materials would expect that such a device would in vivo stimulate the production of fibrous tissue which would block the pores. It is known that when micromachined silicon structures are used as sensors for neural elements a layer of fibrous tissue forms between the silicon surfaces and the neural elements of interest, as reported by D. J. Edell et al. in IEEE Transactions on Biomedical Engineering, Volume 39, Number 6, 1992 page 635. Indeed the thickness and nature of any fibrous tissue layer formed is often used as one measure of biocompatibility, with a thinner layer containing little cell necrosis reflecting a higher degree of biocompatibility.
U.S. Pat. No. 5,225,374 describes the use of porous silicon as a substrate for a protein-lipid film which interacts with target species to produce an electrical current when exposed to target species in an in vitro solution. The porous silicon is oxidised to produce a hydrophilic surface and is chosen since the pores act as a conduit for an ion-current flow and the structure provides structural support for the lipid layer. The porous silicon is separated from the in vitro solution by the protein-lipid film and so the question of the bioactivity or biocompatibility of the porous silicon does not arise.
Porous silicon has been suggested as a substrate material for in vitro biosensors by M. Thust et al. in Meas. Sci. Technol, Volume 7 1996 pages 26-29. In the device structure described therein, the porous silicon is subjected to a thermal oxidation process to form a silicon dioxide layer on the exposed silicon surfaces of the pores. Since the porous silicon is partially thermally oxidised, the bioactivity or biocompatibility of the silicon is not of relevance since it is only the silicon dioxide which is exposed to test solutions. The porous silicon is effectively an inert host for enzyme solutions.
Microperforated silicon membranes have been described as being capable of supporting cell structures by E. Richter et al. in Journal of Materials Science: Materials in Medicine, Volume 7, 1996, pages 85-97, and by G. Fuhr et al. in Journal of Micromechanics and Microengineering, Volume 5, Number 2, 1995, pages 77-85. The silicon membranes described therein comprises silicon membranes of thickness 3 xcexcm perforated by square pores of width 5 xcexcm to 20 xcexcm using a lithography process. Mouse embryo fibroblasts were able to grow on cleaned membranes but adherence of the cells was improved if the membranes were coated with polylysine. This paper is silent as to the bioactivity of the silicon membrane, and there is no mention of an apatite layer having been formed when exposed to the cell culture medium. Indeed, given the dimensions of the pores used, the structure is not likely to exhibit a significant degree of bioactivity. Furthermore, it is accepted by Fuhr et al. that there is still a need to find and develop cell-compatible materials with long term stability.
A. Offenhxc3xa4usser et al. in Journal of Vacuum Science Technology A, Volume 13, Number 5, 1995, pages 2606-2612 describe techniques for achieving biocompabbility with silicon substrates by coating the substrate with an ultrathin polymer film. Similarly, R. S. Potember et al. in Proc. 16th Int. Conf. IEEE Engineering in Medicine and Biology Society, Volume 2, 1994, pages 842-843 describe the use of a synthetic peptide attached to a silicon surface to promote the development of rat neurons.
In a further aspect, the invention provides a bioactive silicon structure characterized in that the silicon is at least partly crystalline.
In a still further aspect, the invention provides an electronic device for operation within a living human or animal body, characterized in that the device includes bioactive silicon.
Bioactive silicon of the invention may be arranged as a protective covering for an electronic circuit as well as a means for attaching a device to bone or other tissue.
The electronic device may be a sensor device or a device for intelligent drug delivery or a prosthetic device.
In a still further aspect, the invention provides a method of making silicon bioactive wherein the method comprises making at least part of the silicon porous.
In another aspect, the invention provides a method of fabricating bioactive silicon, characterized in that the method comprises the step of depositing a layer of polycrystalline silicon.
In a yet further aspect, the invention provides biocompatible silicon characterized in that the silicon is at least partly crystalline.
In a still further aspect, the invention provides resorbable silicon.
In another aspect, the invention provides a method of accelerating or retarding the rate of deposition of a mineral deposit on silicon in a physiological electrolyte wherein the method comprises the application of an electrical bias to the silicon.
The silicon may be porous silicon.
In a further aspect, the invention provides bioactive material characterised in that the bioactivity of the material is controllable by the application of an electrical bias to the material.
Conventional bioactive ceramics are electrically insulating and therefore preclude their use in electrochemical applications. Where the electrical stimulation of tissue growth has been studied previously, it has often been difficult to distinguish the direct effects of electric fields from those associated with an altered body chemistry near implanted xe2x80x9cbioinertxe2x80x9d electrodes.
In a still further aspect, the invention provides a composite structure comprising bioactive silicon region and a mineral deposit thereon characterized in that the silicon region comprises silicon which is at least partly crystalline.
A possible application of the invention is as a substrate for performing bioassays. It is desirable to be able to perform certain tests on pharmaceutical compounds without resorting to performing tests on living animals. There has therefore been a considerable amount of research activity devoted to developing in vitro tests in which cell lines are supported on a substrate and the effects of pharmaceutical compounds on the cell lines monitored. A composite structure of silicon and apatite might provide a suitable substrate for such tests.
In a further aspect, the invention provides a method of fabricating a biosensor, characterized in that the method includes the step of forming a composite structure of bioactive silicon and a mineral deposit thereon.
The invention further provides a biosensor for testing the pharmacological activity of compounds including a silicon substrate, characterized in that at least part of the silicon substrate is comprised of bioactive silicon.